Warfarin dose requirements in Asians can be accurately predicted by use of a combination of patient demographics and a simplified genotyping approach for single variants in CYP2C9 and VKORC1.

Purpose: This tumor response pharmacodynamic model aims to describe primary lesion shrinkage in non^small cell lung cancer over time and determine if concentration-based exposure metrics for gemcitabine or that of its metabolites, 2 ¶,2 ¶-difluorodeoxyuridine or gemcitabine triphosphate, are better than gemcitabine dose for prediction of individual response. Experimental Design: Gemcitabine was given thrice weekly on days 1 and 8 in combination with carboplatin, which was given only on day 1of every cycle. Gemcitabine amount in the body and area under the concentration-time curves of plasma gemcitabine, 2 ¶,2 ¶-difluorodeoxyuridine, and intracellular gemcitabine triphosphate in white cells were compared to determine which best describes tumor shrinkage over time. Tumor growth kinetics were described using a Gompertzlike model. Results: The apparent half-life for the effect of gemcitabine was 7.67 weeks. The tumor turnover time constant was 21.8 weekÁcm. Baseline tumor size and gemcitabine amount in the body to attain 50% of tumor shrinkage were estimated to be 6.66 cm and 10,600 mg. There was no evidence of relapse during treatment. Conclusions: Concentration-based exposure metrics for gemcitabine and its metabolites were no better than gemcitabine amount in predicting tumor shrinkage in primary lung cancer lesions. Gemcitabine dose-based models did marginally better than treatment-based models that ignored doses of drug administered to patients. Modeling tumor shrinkage in primary lesions can be used to quantify individual sensitivity and response to antitumor effects of anticancer drugs.

The saturability of dFdCTP accumulation in Arm A suggests optimal delivery of gemcitabine is achieved using fixed rate infusion compared to 30-min infusion. Fixed dose rate gemcitabine is active and feasible, supporting the concept of fixed dosing rate of gemcitabine in advanced NSCLC. However, this entails a longer infusion time with associated higher costs involved.

Ixekizumab (LY2439821), a humanized immunoglobulin G subclass 4 (IgG4) monoclonal antibody that selectively binds and neutralizes interleukin (IL) 17A has demonstrated efficacy in the treatment of psoriasis. A population pharmacokinetics-pharmacodynamics model was developed using NONMEM 7.2 to describe the temporal relationship between ixekizumab concentrations and absolute Psoriasis Area and Severity Index (PASI) scores from a phase 2 dose-finding study in chronic plaque psoriasis. The objective was to inform dose-selection for further development. The primary endpoint, PASI 75 (75% or greater improvement from baseline PASI score) was then derived from each individual's absolute PASI score. The population pharmacokinetics of ixekizumab was characterized by a two-compartment model, while the exposure-response relationship was characterized using an indirect response model that described the pharmacological effects of ixekizumab and placebo in the form of inhibition of the formation of psoriatic skin lesions. PASI 75 responder status at the Week 12 primary endpoint was found to be a significant covariate on the concentration producing half maximal effect (EC50 ). While the results suggested patient may have different levels of sensitivity to ixekizumab, it is possible that nonresponder patients assigned to lower doses of ixekizumab may potentially become responders to ixekizumab if given doses that yield adequate exposures.

The results showed that first-order and nonsaturable clearance described intracellular dFdCTP formation at clinically applied doses of gemcitabine.

Fixed dosing was found to be feasible, without increased variability of clearance or neutrophil toxicity compared to BSA-based dosing. With ketoconazole modulation, docetaxel clearance correlated with renal function but not CYP3A phenotype.

Purpose:This study aims to describe a population pharmacokinetic model for docetaxel in Asian breast cancer patients and to evaluate the effects of single-nucleotide polymorphisms (SNP) in the cytochrome P450 3A (CYP3A) gene expression regulators, constitutive androstane receptor (CAR), pregnane X receptor (PXR), and hepatic nuclear factor 4a (HNF4a), on the pharmacokinetics of docetaxel. Experimental Design: Docetaxel was given as an i.v. infusion of 75 mg/m 2 over 1 h to 101 female breast cancer patients. CAR, PXR, and HNF4a were comprehensively sequenced. Docetaxel concentrations were measured using a liquid chromatography/tandem mass spectrometry method and its population pharmacokinetic variables, and the covariate effects of clearance predictors were estimated using a nonlinear mixed effects model. Results: Final estimates for docetaxel clearance was 47.1 L/h/70 kg/1.75 m. Between subject variability in docetaxel clearance was 22.5%. Covariates that showed significant association with docetaxel clearance included body size, a1acid glycoprotein and liver function. SNPs identified in the coding regions of CAR and HNF4a and 5 ¶ untranslated region of PXR in this Asian breast cancer cohort did not seem to improve predictability of docetaxel clearance. Conclusions: SNPs identified in CYP3A gene expression regulators CAR, HNF4a, and PXR in the Asian female breast cancer population do not seem to have any significant effect on the clearance of docetaxel, a CYP3A substrate.

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